tbuckley/cabot-search huggingface dataset:
Abstract LB169: Machine learning-based approach for glioblastoma drug repurposing on real-world patient data
Authors: Ko-Hong Lin, Yejin Kim, Dung-Fang Lee, Xiaoqian Jiang
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most aggressive and deadly type of brain cancer. The poor survival rate of GBM is often attributed to the low therapeutic efficiency of current front-line therapy, treatment resistance, and high recurrence rate. Sizeable clinical data of cancer patients preserve a great potential for drug discovery and drug repurposing research, enabling comprehensive screening of treatment effects among frequently-prescribed medications. To efficiently characterize potent drug candidates and develop novel treatment strategies for GBM, we designed a machine-learning-based pipeline that predicts repurposable drug combinations from large-scale patient claims data. Our pipeline first identified pseudo-randomized drug-user and non-user cohorts from heterogeneous clinical records and balanced the confounding effects using the Inverse Probability of Treatment Weighting (IPTW) method. Next, our model computed the averaged treatment effect on the treated (ATT) values to determine the treatment effects of our candidates. Our methodology identified several promising drug combinations that have been found to be effective in inhibiting GBM in cell line experiments. This research was conducted by integrating computational and experimental approaches to identify drug combinations, providing a promising strategy for the development of new treatments for GBM. Citation Format: Ko-Hong Lin, Yejin Kim, Dung-Fang Lee, Xiaoqian Jiang. Machine learning-based approach for glioblastoma drug repurposing on real-world patient data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB169.
Abstract LB173: A bioinformatics approach to determine the potential benefit of blocking both Galectin-1 and Galectin-3 in cancer
Authors: Ian Holyer, Rob Slack
Journal: Cancer Research (2023)

Abstract Galectins are a family of Beta-galactoside-binding lectins that control numerous cellular processes in health and disease, including fibrosis, carcinogenesis and tumour immune evasion. Evidence is starting to emerge that blockade of more than one galectin may provide additional benefit within the oncology arena due to the overlapping biological functions associated with these lectins. Due to the rich and robust external datasets associated with the two most previously studied galectins, we initially investigated the potential therapeutic benefit of a dual blockade approach of Galectin-1 (Gal-1) and Galectin-3 (Gal-3). A systematic assessment, consisting of three steps, was implemented to conclude the potential clinical effects of dual Gal-1 and Gal-3 inhibition and the specific cancers which may benefit the most from this approach. Step 1 consisted of pathway map reconstructions, depicting the role of Gal-1 and Gal-3 in tumor invasion, metastasis and angiogenesis, to confirm overlapping and independent cancer pathways associated with both galectins. These maps were constructed based on evidence from published literature and additional external databases. Step 2 aligned and ranked the associated expression of Gal-1 and Gal-3 at both the mRNA and protein level across different cancer types. This profiling included data from publicly available TCGA and CPTAC databases and additional external sources. Step 3 tested the highest ranked Gal-1 and Gal-3 mRNA and protein expressing cancers for association of survival by stratifying patients into four cohorts: Gal-1 low/Gal-3 low, Gal-1 high/Gal-3 low, Gal-1 low/Gal-3 high, Gal-1 high/Gal-3 high. Survival profiles quite clearly show that high expression of both galectins leads to poor survival in certain cancer types but not all. To summarize, using a bioinformatics approach, we have provided the initial evidence that Gal-1 and Gal-3 are highly expressed at both the gene and protein level in several cancers with their combined expression strongly correlating with poor survival rates. This data suggests, in certain cancer types, that targeting dual inhibition of Gal-1 and Gal-3 will have the potential to improve patient survival to a greater extent than a single Galectin blockade approach. Citation Format: Ian Holyer, Rob Slack. A bioinformatics approach to determine the potential benefit of blocking both Galectin-1 and Galectin-3 in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB173.
Abstract LB326: Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas
Authors: Maria Alejandra Gonzalez, Joseph Kissil, Scott Troutman
Journal: Cancer Research (2023)

Abstract Neurofibromatosis type 2 (NF2) is a rare disorder that is inherited in an autosomal-dominant manner and is attributed to the loss of heterozygosity (LOH) of the NF2 gene, which encodes for the tumor suppressor protein Merlin. Patients affected by the disease develop vestibular schwannomas (VS), meningiomas, and ependymomas resulting in high morbidity and premature mortality. To date, neurofibromatosis type 2 has no FDA-approved drug-based treatment. Merlin plays a central role in mediating cell contact inhibition (CI) of proliferation. Loss of Merlin leads to abnormal activation of multiple signaling pathways, including those regulated by small G-proteins Ras/Rac/cdc42 and the Hippo-YAP pathway. The Hippo-YAP pathway plays a major role in cell growth and organ size control and at its core is comprised of a kinase cascade that regulates the transcriptional regulator YAP. The function of YAP is crucial for VS development, and there are several mechanisms by which YAP regulates transcription. Some of these functions have been shown to involve the Bromodomain and Extra-Terminal domain (BET) proteins acting as co-factors. We have previously shown that the BET inhibitor JQ1 can selectively reduce the growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo. Additionally, evidence has shown that Merlin loss can lead to increased cell proliferation that it requires the activity of Focal Adhesion Kinase 1 (FAK1). We have previously demonstrated that FAK1 inhibition via Crizotinib has antiproliferative effects in NF2-null Schwann cells, and is currently in phase II clinical trials in NF2-related VS. In this study, wild-type and NF2-null Schwann cells and schwannoma cell lines were used to determine the impact on cell growth by employing the treatment with the BET inhibitor JQ1 and the FAK1 inhibitor Crizotinib. Our analysis in NF2-null Schwann cells and schwannoma cell lines shows that the combined inhibition exerts an antineoplastic effect at nanomolar concentrations. Moreover, this combination resulted in selective inhibition of NF2-null Schwann cell proliferation when compared to wild-type Schwann cells in vitro, when compared to either drug alone. Our preliminary data suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas. Citation Format: Maria Alejandra Gonzalez, Joseph Kissil, Scott Troutman. Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB326.
Abstract LB239: Downregulation of spliceosomal proteins hnRNPH1 and H2 in WM266-4 melanoma cells induces immune signaling
Authors: Maab Sultan, Juan Diez, Keiran S.M. Smalley, Vladimir Beljanski, Lubov Nathonson, Dmitriy Minond
Journal: Cancer Research (2023)

Abstract This study aims to determine the effect of hnRNPH1/H2 (H1/H2) downregulation on immune-related genes in vitro. Due to the molecular heterogeneity of melanoma, it is difficult to treat it, which necessitates new approaches. We discovered compounds that selectively kill melanoma cells by binding to spliceosomal proteins hnRNPH1/H2. RNAseq of melanoma cells treated with H1/H2 siRNA showed upregulation of immune pathways. To validate this effect of genomic modulation of H1/H2 on immune gene expression, we used NanoString method. We treated both WM266-4 cell line and melanocytes with H1/H2 siRNA and scrambled siRNA to knockdown our target gene. Then, RNA was extracted and analyzed by NanoString. Analysis data of melanoma cell line showed a significant difference between RNA samples treated with scrambled and the one treated with siRNA in upregulating immune-related genes. In contrast, data of melanocytes revealed no significant difference between scrambled and siRNA samples and did not show upregulation of these genes. This implies the specificity of this response to melanoma cells. In conclusion, we hypothesize that downregulation of spliceosomal proteins H1/H2 can upregulate immune-related genes, which in turn can improve melanoma patients’ survival. Consequently, H1/H2 can be targeted as a novel therapeutic approach. Citation Format: Maab Sultan, Juan Diez, Keiran S.M. Smalley, Vladimir Beljanski, Lubov Nathonson, Dmitriy Minond. Downregulation of spliceosomal proteins hnRNPH1 and H2 in WM266-4 melanoma cells induces immune signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB239.
Abstract LB039: Ovarian cancer cell-derived exosomal UCA1 reprograms glucose metabolism in stromal fibroblasts
Authors: Revathy Nadhan, Ji Hee Ha, Muralidharan Jayaraman, Srishti Kashyap, Danny N. Dhanasekaran
Journal: Cancer Research (2023)

Abstract Tumor progression is stringently regulated by the co-ordinated signaling between the tumor cells and the tumor microenvironment (TME) through diverse autocrine, paracrine and exocrine signaling mechanisms. Recent studies have shown that the exosomes that play a crucial role in the transfer of oncogenic macromolecules and oncometabolites to different cellular components of the TME can be targeted for therapy. Therefore, with the focus on identifying the exosomal long non-coding RNA (lncRNA) that can be therapeutically targeted, we investigated the profile of ovarian cancer cell derived lncRNAs and their functional role in ovarian cancer pathophysiology. Analysis of exosomes derived from a panel of high grade serous ovarian cancer cell lines indicated that UCA1 (Urothelial Cancer Associated 1) is the most abundantly packaged lncRNA in the exosomes. Similarly, exosomes from patient-derived ovarian cancer cells exhibited higher levels of UCA1. Ascites from ovarian cancer patients also indicated high levels of UCA1 in the ascites-derived exosomes. Results using PKH67-labelled ovarian cancer cell-derived exosomes and MRC5 fibroblast cell line indicated the exosomal transfer of UCA1 to the fibroblasts. Since paracrine signaling has been shown to induce metabolic reprogramming of peritumoral fibroblasts, we interrogated whether exosomal transfer of UCA1 could reprogram the glucose metabolism in the fibroblasts. Results from the Agilent Seahorse glycolytic stress assay indicate that the exosomal UCA1 promotes reprogramming of glucose metabolism in fibroblast cells while depleting of UCA1 in the exosomes failed to induce such metabolic reprogramming. Results from the analysis of the key glycolytic enzymes in the stromal fibroblasts, post-exosomal UCA1 uptake also corroborate this conclusion. Thus our results provide primary evidence that the exosomal-UCA1 induces pro-tumorigenic metabolic reprogramming in peri-tumoral fibroblasts. Together with the known oncogenic role of UCA1 in many different cancer cells, our findings indicate that targeting UCA1 could form a productive precision cancer strategy in ovarian cancer, targeting both the tumor cells and tumor stromal cells. This research was supported by the Department of Defense Ovarian Cancer Research Program Award W81XWH-18-1-0066, W81XWH-22-1-0415, the National Institute of General Medical Sciences grant P20 GM103639 and The National Cancer Institute of the National Institutes of Health grant P30 CA225520. Citation Format: Revathy Nadhan, Ji Hee Ha, Muralidharan Jayaraman, Srishti Kashyap, Danny N. Dhanasekaran. Ovarian cancer cell-derived exosomal UCA1 reprograms glucose metabolism in stromal fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB039.
Abstract LB034: EWSR1, Ewing sarcoma breakpoint region 1, maintains centromere identity by binding to centromeric R-loops
Authors: Risa Kitagawa, Argentina Becker, Peter Houghton, Katsumi Kitagawa
Journal: Cancer Research (2023)

Abstract The centromere DNA-kinetochore complex is the specialized chromatin structure that mediates chromosome attachment to microtubules and is required for high-fidelity chromosome transmission. CENP-A is the centromere-specific histone H3 variant that epigenetically determines centromere position on the chromosome to ensure kinetochore assembly. Despite its importance, the precise mechanism of maintenance of CENP-A, i.e., the maintenance of centromere identity, remains obscure. In this study, we found that EWSR1 (Ewing Sarcoma Breakpoint Region 1) is required for CENP-A deposition at centromeres by binding to centromeric RNA. We determined that the CENP-A binding domain of EWSR1 is the SYGQ2 region within the prion-like domain, which plays an important role in phase separation for chromatin remodeling. Our data suggest that EWSR1 guards CENP-A in centromeric chromatins by binding to centromeric RNA. This is a novel mechanism to maintain the position of the centromere on the chromosome i.e., centromere identify. As EWSR1-FLI1 is the oncogenic fusion protein in Ewing sarcoma and as it inhibits EWSR1 function as a dominant negative mutant, it contributes to chromosome instability in Ewing sarcoma, which may lead to therapy resistance and metastasis. Citation Format: Risa Kitagawa, Argentina Becker, Peter Houghton, Katsumi Kitagawa. EWSR1, Ewing sarcoma breakpoint region 1, maintains centromere identity by binding to centromeric R-loops [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB034.
Abstract LB238: Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors
Authors: Kenji Tanabe
Journal: Cancer Research (2023)

Abstract The gene encoding epidermal growth factor receptor (EGFR) is a major driver gene in cancer. Many drugs targeting EGFR-associated molecules have been developed, yet many have failed in clinical trials due to a lack of efficacy and/or unexpected side effects. In this study, I used image-based phenotypic profiling to screen a pharmacologically active compound library with the aim of identifying new druggable targets in the EGFR pathway. As anticipated, the phenotypic screen identified compounds that produce phenotypes resulting from targeting a known specific molecule or pathway. The assay also showed that compounds with diverse known mechanisms of action produced similar, EGFR-related cellular phenotypes. Biochemical assays revealed that those compounds share a previously unappreciated common target/pathway, showing that the image-based assay can identify new target molecules that are independent of the compound’s known target. Citation Format: Kenji Tanabe. Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB238.
Abstract LB036: IRF8 regulates tumor cell sensitivity to intrinsic ferroptosis by repressing p53
Authors: Dakota Poschel, Mercy Kehinde-Ige, John Klement, Dafeng Yang, Alyssa Merting, Natasha Savage, Huidong Shi, Kebin Liu
Journal: Cancer Research (2023)

Abstract Tumor cell resistance to ferroptosis, which is a recently discovered CTL induced cell death pathway, remains incompletely understood. We report here that interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis. Genome-wide gene expression profiling identified ferroptosis pathway as an IRF8-regulated pathway in tumor cells. IRF8.KO tumor cells are resistant to intrinsic ferroptosis induction and also exhibit decreased ferroptosis in response to tumor specific CTL killing. Loss of IRF8 increases p53 express in tumor cells and knocking out Tp53 in IRF8.KO cells restored tumor cell sensitivity to intrinsic ferroptosis induction. We were able to show that treating tumor-bearing mice with IRF8-encoding plasmid NTC9385R-mIRF8 encapsulated in a DOTAP-cholesterol lipid nanoparticle significantly reduced tumor growth and increased the percentage of dead cells in the tumor. Our data therefore determine that IRF8 represses p53 expression to maintain tumor cell sensitivity to intrinsic ferroptosis. Citation Format: Dakota Poschel, Mercy Kehinde-Ige, John Klement, Dafeng Yang, Alyssa Merting, Natasha Savage, Huidong Shi, Kebin Liu. IRF8 regulates tumor cell sensitivity to intrinsic ferroptosis by repressing p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB036.
Abstract LB032: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2
Authors: Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Junwei Lian, Wenliang Li
Journal: Cancer Research (2023)

Abstract Treatment-related neuroendocrine prostate cancer (t-NEPC, here as NEPC) is an aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% of lethal CRPC. The mechanisms underlying the progression of prostate cancer to NEPC are largely unclear, and new drug targets are desperately needed. NEPC is known to be highly vascularized. Elevated expression of NE markers and increased angiogenesis are two prominent phenotypes of NEPC, and thus are expected to be linked. However, direct molecular links between these two phenotypes are still elusive, whose elucidation will substantially expand our knowledge in NEPC and enable the development of effective treatments for NEPC. Through RNAi &amp; cDNA screening and functional validations, we previously discovered that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. The mechanisms of GRK3 in prostate cancer progression were mostly unknown. Our new data indicate that GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in NEPC. GRK3 promotes both angiogenesis and neuroendocrine differentiation in prostate cancer cells, indicating that it is a key missing link for these two phenotypes. Mechanistically, GRK3 enhances the epigenetic repressor activity of histone deacetylase 2 (HDAC2) to suppress key repressors of angiogenesis or NE phenotype. Through compound library screening, we have identified several compounds that block kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could substantially reduce angiogenesis and NE marker expression, as well as significantly inhibit NEPC cell growth in culture and in mouse xenografts. In summary, kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression. Its mechanism of actions is at least in part through enhancing HDAC2’s epigenetic activity. Results based on our novel GRK3 inhibitors suggest that GRK3 is a valuable new drug target for aggressive prostate cancer. Citation Format: Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Junwei Lian, Wenliang Li. Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB032.
Abstract LB010: LY6K depletion modulates TGF-β and EGF signaling
Authors: Young Yang, Sujeong Park
Journal: Cancer Research (2023)

Abstract Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) signaling through clathrin- and caveolin-1 (CAV-1)-mediated endocytosis. LY6K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-β-enhanced migration and invasion. Both TGF-β receptor-I (TβRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TβRI irrespective of the presence of TGF-β; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired SMAD2 phosphorylation upon TGF-β treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TβRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. Subsequently, transmission electron microscopy showed no clathrin and CAV-1-coated vesicles in LY6K-depleted cells. Our study demonstrates the key role of LY6K in both clathrin- and CAV-1-mediated endocytic pathways regulated by TGF-β and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival. Citation Format: Young Yang, Sujeong Park. LY6K depletion modulates TGF-β and EGF signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB010.